Antiinflammatory-4,5-diphenyl-2-substituted-thio-imidazoles and their corresponding sulfoxides and sulfones

ABSTRACT

Imidazole derivatives of the formula ##STR1## wherein Ar 1  and Ar 2  are each phenyl; phenyl substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy or C 2-6  dialkylamino; pyridyl; furyl; or thienyl; with the proviso that Ar 1  and Ar 2  are not both unsubstituted phenyl; 
     R 1  is hydrogen, C 1-4  alkyl or C 1-4  alkyl substituted by hydroxy, C 1-4  alkoxy or C 1-6  alkanoyloxy; 
     n is 0, 1 or 2; and 
     Z is a C 2-6  -alkyl or -alkenyl residue substituted by one or two of hydroxy, C 1-4  alkoxy, C 2-8  alkylenedioxy, C 1-6  alkanoyloxy or benzoyloxy, or by one alkoxycarbonyl group; 
     and the salts thereof with physiologically acceptable acids, possess valuable pharmacological properties.

BACKGROUND OF THE INVENTION

The present invention relates to novel imidazole derivatives, a processfor their preparation and pharmaceutical preparations containing them asthe active ingredients.

SUMMARY OF THE INVENTION

It is an object of this invention to provide new imidazoles havingpharmacological effectiveness.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

These objects have been attained by providing imidazoles of formula I##STR2## wherein

Ar₁ and Ar₂ are each phenyl; phenyl substituted by halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy or C₂₋₆ dialkylamino; pyridyl; furyl; or thienyl; with theproviso that Ar₁ and Ar₂ are not both unsubstituted phenyl;

R₁ is hydrogen, C₁₋₄ alkyl or C₁₋₄ alkyl substituted by hydroxy, C₁₋₄alkoxy or C₁₋₆ alkanoyloxy;

n is 0, 1 or 2; and

Z is a C₂₋₆ -alkyl or -alkenyl residue substituted by one or two ofhydroxy, C₁₋₄ alkoxy, C₂₋₈ alkylenedioxy, C₁₋₆ alkanoyloxy orbenzoyloxy, or by one alkoxycarbonyl group;

and the salts thereof with physiologically acceptable acids.

DETAILED DISCUSSION

According to this invention, the substituents Ar₁ and Ar₂ of theimidazole derivatives are each phenyl optionally substituted by halogen(F, Cl, Br, I), alkyl, alkoxy or dialkyl-amino; pyridyl; furyl; orthienyl. Suitable phenyl residues Ar₁ and Ar₂ substituted by halogenatoms include, for example, mono- or difluorophenyl and mono- ordichlorophenyl, and, in particular, para-fluorophenyl orpara-chlorophenyl. Alkyl-substituted phenyl residues include,preferably, those having alkyl groups of 1-4 carbon atoms (for example,methyl, ethyl, propyl or isopropyl groups). Phenyl residues substitutedby alkoxy groups include, preferably, those having alkoxy groups of 1-4carbon atoms, (e.g., methoxy, ethoxy, propoxy or isopropoxy groups).Phenyl residues substituted by dialkylamino groups include, preferably,those having dialkylamino residues of 2-6 total carbon atoms; forexample, dimethylamino, methylethylamino or diethylamino. Preferably,1-2 substituents can be included on each phenyl nucleus.

The substituents Ar₁ and Ar₂ can be alike or different providing thatboth substituents are not unsubstituted phenyl.

R₁ is hydrogen or alkyl of 1-4 carbon atoms optionally substituted byhydroxy groups, alkoxy groups or acyloxy groups. Preferably, thesubstituent R₁ represents an unsubstituted alkyl group or an alkyl groupsubstituted in the 2-position by an hydroxy group, by an alkoxy group of1-4 carbon atoms (e.g., methoxy, ethoxy, propoxy or isopropoxy) or by analkanoyloxy group of 1-6 carbon atoms (e.g., formyloxy, acetoxy,propionyloxy, or butyryloxy). In particular, the substituent R₁ may behydrogen or methyl.

The substituent Z can be an unsaturated or preferably saturated,preferably aliphatic acyclic hydrocarbon residue of 2-6 carbon atomssubstituted by one or two of the following groups: hydroxy groups,alkoxy groups, alkylenedioxy groups or acyloxy groups, or by onealkoxycarbonyl group. The unsubstituted hydrocarbon moiety, thus,generally is a residue of an alkane or alkene or equivalents thereof.Preferably, the Z hydrocarbon residue is of 1-3 carbon atoms, mostpreferably a C₁₋₃ alkyl residue, and especially ethyl.

Suitable alkoxy groups of substituent Z (including those on thealkoxycarbonyl group) preferably contain 1-4 carbon atoms, e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, or tert-butoxy. SuitableC₂₋₈ alkylenedioxy groups of substituent Z include those wherein thedioxy portion is connected to the Z hydrocarbon residue, e.g.,preferably alkylenedioxy groups of 2-6 total carbon atoms, including anypendant alkyl groups such as, for example, the 1,2-ethylenedioxy group,the 1,3-propylenedioxy group or the 2,2-dimethylpropylenedioxy group; aswell as those wherein the dioxy portion is not connected to the Zhydrocarbon residue, e.g., preferably, 1,3-dioxolan-2-yl or di-C₁₋₄-alkoxy methylene. Suitable acyloxy groups of substituent Z includepreferably those groups derived from an aliphatic, preferably saturatedcarboxylic acid of 1-6 carbon atoms, such as formic acid, acetic acid,propionic acid, butyric acid, isobutyric acid, trimethylacetic acid,valeric acid, etc. (i.e., C₁₋₆ alkanoyloxy) or from benzoic acid.Equivalents of all these groups are also included.

The substituents of residue Z are preferably in the 2- or 3-position ofthe hydrocarbon residue. Preferably, the total number of allsubstituents on any Z residue is 1-2.

Especially preferred compounds are those wherein substituents Ar₁ andAr₂ each are phenyl; phenyl substituted in the para position byfluorine, chlorine, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbonatoms or dialkylamino of 2-6 carbon atoms; 2-pyridyl; 2-furfuryl; or2-thienyl; e.g., phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,4-methoxyphenyl, 4-dimethylaminophenyl, 2-pyridyl or 2-thienyl; and/orwherein the substituent Z is a C₂₋₆ -alkyl or -alkenyl residuesubstituted by one or two hydroxy groups attached to different carbonatoms; by C₁₋₄ alkoxy; by C₁₋₆ alkanoyloxy or by benzoyloxy; e.g.,2-hydroxyethyl; e.g., a C₁₋₃ -alkyl or -alkenyl residue substituted by1,3-dioxaolan-2-yl or by a dialkoxymethylene group of 1-4 carbon atomsin each alkoxy group; e.g., a C₁₋₃ -alkyl or -alkenyl residuesubstituted by a C₁₋₄ alkoxycarbonyl group.

Physiologically acceptable salts of the imidazole derivatives of formulaI include, for example, the salts of hydrogen chloride, hydrogenbromide, or hydrogen iodide; of sulfuric acid or phosphoric acid; orsalts of organic acids, such as formic acid, acetic acid, succinic acid,maleic acid, tartaric acid or citric acid.

The novel imidazole derivatives of formula I can be prepared byfollowing fully conventional methods such as those outlined below. Thesecan be conducted under fully conventional conditions as described, e.g.,in Liebigs Annalen 284, 1894: 9 et seq.; J. Chem. Soc. 1931: 3043 etseq.; J. Med. Chem. 20, 1977: 563 et seq.; Liebigs Annalen 214, 1882:257 et seq.; J. Chem. Soc. 1942: 232 et seq.; J. Chem. Soc. 1963: 2195et seq. Houben-Weyl: "Methoden der organischen Chemie" [Methods ofOrganic Chemistry] vol. IX: 229 et seq.; Bull. Soc. France 1977: 271 etseq.; and DOS No. 2,635,876.

Typical processes for preparing the imidazole derivatives of formula Iinclude those wherein, in a conventional manner:

(a) an imidazole derivative of formula II ##STR3## wherein Ar₁, Ar₂ andR₁ are as defined above, is condensed with a compound of formula III

    WZ                                                         (III)

wherein

Z is as defined above and

W is a halogen atom, an alkylsulfonyloxy residue or an arylsulfonyloxyresidue;

or

(b) for the preparation of imidazole derivatives of Formula I wherein Zis ##STR4## wherein

R₂, R₃, R₄ and R₅ are hydrogen atoms or hydrocarbon residues of, intotal, 1-4 carbon atoms optionally substituted by hydroxy, alkoxy,alkylenedioxy or acyloxy,

an epoxide of formula IV ##STR5## wherein R₂, R₃, R₄ and R₅ are asdefined above,

is added chemically to an imidazole derivative of formula II;

or

(c) for the preparation of imidazole derivatives of formula I wherein Zis

    --CR.sub.4 ═CHR.sub.2

wherein R₂ and R₄ are as defined above, an ethynyl compound of formula V

    R.sub.4 C.tbd.CR.sub.2                                     (V)

wherein R₂ and R₄ are as defined above,

is chemically added to an imidazole derivative of formula II;

and optionally the thio compounds of formula I obtained according toprocess variations (a) through (c) are oxidized to the correspondingsulfinyl compounds or sulfonyl compounds;

optionally the alkoxycarbonyl compounds obtained according to processvariations (a) through (c) are reduced to the correspondinghydroxymethyl compounds;

imidazole derivatives unsubstituted in the 1-position are alkylated;

imidazole derivatives containing hydroxy groups are esterified; and/or

imidazole derivatives of formula I are converted into the salts thereofwith physiologically acceptable acids.

After the synthesis has been accomplished, the racemic imidazolederivatives of formula I can be split into their optical antipodes byconventional processes, for example, by chromatographing these productsby column chromatography on optically active carriers (e.g.,"Sephadex").

The starting compounds for the processes of this invention are known orcan be prepared by conventional methods (Synthesis 1976: 733 et seq. andZhur.Obsch.Khim 31, 1961: 1039 et seq.). Such methods for producingthese starting compounds are illustrated hereinbelow with reference toseveral typical compounds:

A solution of 20.43 g. of 4-dimethylaminobenzoin in 250 ml. ofdimethylformamide is combined with 12.18 g. of ammonium thiocyanate; themixture is heated for 14 hours to 80° C. After cooling, the solution isstirred into ice water; the thus-precipitated crystals arevacuum-filtered and recrystallized from hot ethanol, thus obtaining14.62 g. of 4-(4-dimethylamino)-5-phenyl-2-mercaptoimidazole, m.p.277°-280° C.

A solution of 4.04 g. of 2-pyridoin in 50 ml. of dimethylformamide iscombined with 3.04 g. of ammonium thiocyanate, and the solution isheated for 12 hours to 80° C. After cooling, the solution is stirredinto ice water; the thus-precipitated crystals are vacuum-filtered andrecrystallized from hot ethanol, thus obtaining 4.70 g. of4,5-bis-(2-pyridyl)-2-mercaptoimidazole, m.p. 285°-287° C.

A solution of 11.2 g. of 2-thiophenoin in 150 ml. of dimethylformamideis combined with 7.6 g. of ammonium thiocyanate, and the solution isheated for 8 hours to 80° C. After cooling, the solution is stirred intoice water; the thus-precipitated product is vacuum-filtered andrecrystallized from hot ethanol, thus obtaining 7.23 g. of4,5-di(2-thienyl)-2-mercaptoimidazole, m.p. 300°-301° C.

The imidazole derivatives of formula I are distinguished by a pronouncedantiinflammatory and antiallergic activity in mammals, including humans.This effect is especially striking in the imidazole derivativesmentioned as preferred above.

Moreover, the imidazole derivatives of formula I are distinguished byexhibiting a very favorable dissociation between desirablepharmacological efficacy and undesirable--especially ulcerogenic--sideeffects. This dissociation is especially pronounced in those imidazolederivatives of formula I wherein n is 1 or 2.

The antiinflammatory effectiveness of the compounds of this inventioncan be determined with the aid of the conventional adjuvant arthritistest which is conducted as follows:

Female and male rats of the Lewis strain (LEW) are used and weighbetween 110 and 190 g. The animals receive drinking water and pressedfeed "Altromin" ad libitum.

For each dose group, 10 rats are employed.

Mycobacterium butyricum by Difko, Detroit, is used as the irritant. Asuspension of 0.5 mg. of Mycobacterium butyricum in 0.1 ml. of thinlyfluid paraffin (DAB [German Pharmacopoeia] 7) is injected at asubplantar location into the right hind paw. The test compounds aregiven orally starting with the 11th day of the test daily over a periodof 4 days. The compounds are administered as a clear aqueous solution oras a crystalline suspension with the addition of Myrj 53 (85 mg. %) inan isotonic sodium chloride solution.

Test Setup:

The rats are divided as uniformly as possible with respect to their bodyweight into various groups. After measuring the volume of the right hindpaw by plethysmography, 0.1 ml. of adjuvant is injected into the paw inthe subplantar region. The right hind paws are measured from the 14thday of the experiment until the end of the test. The duration of theexperiment is 3 weeks.

The healing of the hind paws attained with the predetermined dose isrecorded.

A frequent complication in the therapy with non-steroidalantiinflammatory agents is the occurrence of stomach ulcerations. Thisside effect can be demonstrated by animal experiment, determining at agiven dose the number of lesions observed and the total area thereof.The ulcer test is conducted as follows.

Male Wistar rats (SPF) are utilized. The animals are in a weight rangeof 130±10 g. Sixteen hours prior to commencing the experiment, theanimals are put on a fast; they receive water ad libitum.

Per dose, 5 animals are employed. The substances are applied onceorally, dissolved in a sodium chloride solution or as a crystallinesuspension with the addition of 85 mg. % Myrj 53.

Three hours after administration of the compound, 1 ml. of a 3% solutionof the dye pure diphenyl blue is injected intravenously, and the animalis sacrificed. The stomach is resected and examined microscopically withrespect to the number and total size of epithelial lesions and ulcers,which are brought out by dye accumulations.

The factor by which the lesions have multiplied in number and the areaas compared with the lesions of the correspondingly treated controlanimals are determined.

The following table shows the results obtained in these tests with thecompound of this invention as compared with the previously knowncompound indomethacin (compound 1) and with the structurally analogouscompounds 2 and 3 known from DOS [German Unexamined Laid-OpenApplication] No. 2,635,876.

                                      TABLE                                       __________________________________________________________________________                         Adjuvant Arthritis Test                                                                   Ulcus Test                                                       Dose in                                                                             % Healing of                                                                         Dose in                                                          mg./kg.                                                                             Right Hind                                                                           mg./kg.                                                                            Factor for                              No.                                                                              Compound         Animal                                                                              Paws   Animal                                                                             Number                                                                             Area                               __________________________________________________________________________    1  Indomethacin     4 × 4 mg.                                                                     48-58%  8 mg.                                                                             over 20                                                                            over 30                            2  4,5-Bis(4-methoxyphenyl)-                                                     2-ethylthioimidazole                                                                           4 × 50 mg.                                                                    46%    200 mg.                                                                            13.5 30                                 3  4,5-Bis(4-methoxyphenyl)-                                                     2-ethylsulfonylimidazole                                                                       4 × 50 mg.                                                                    53%    200 mg.                                                                            4.5  4.5                                4  4,5-Bis(4-methoxyphenyl)-                                                     2-(2-hydroxyethylthio)-                                                                        4 × 50 mg.                                                                    45%    200 mg.                                                                            4.4  8.7                                   imidazole                                                                  5  4,5-Bis(4-methoxyphenyl)-2-                                                   (2-hydroxyethylsulfinyl)imidazole                                                              4 × 50 mg.                                                                    52%    200 mg.                                                                            1.0  1.0                                6  4,5-Bis(4-methoxyphenyl)-2-                                                   (2-hydroxyethylsulfonyl)imidazole                                                              4 × 50 mg.                                                                    51%    200 mg.                                                                            1.2  1.2                                7  4,5-Bis(4-chlorophenyl)-2-                                                    (2-hydroxyethylsulfonyl)imidazole                                                              4 × 50 mg.                                                                    49%    200 mg.                                                                            0.5  0.5                                8  4,5-Bis(4-methoxyphenyl)-2-                                                   (2,2-dimethoxyethylsulfonyl)-                                                                  4 × 50 mg.                                                                    49%    200 mg.                                                                            2.6  2.3                                   imidazole                                                                  9  [4,5-Bis(4-methoxyphenyl)-                                                    2-imidazolyl]-(1,3-dioxolan-                                                                   4 × 50 mg.                                                                    45%    200 mg.                                                                            1.8  1.8                                   2-yl-methyl)sulfone                                                        __________________________________________________________________________

Surprisingly, there are, among the compounds of this invention, alsothose possessing in addition to the anti-inflammatory efficacy also apronounced antiulcerogenic and tumor-inhibiting effectiveness.

Thus, rats receiving, in addition to 8 mg./kg. of body weight of4,5-bis(4-methoxyphenyl)-2-(2-hydroxyethylsulfinyl)-imidazole showstomach lesions which are significantly reduced in number and area ascompared with a corresponding control group wherein only indomethacinwas administered.

On the other hand, a dose of 50 mg./kg. of animal ofbis(4-methoxyphenyl)-2-(2-hydroxyethylsulfinyl)imidazole cansignificantly suppress tumor formation in rats infected with 100,000Ehrlich tumor cells.

Accordingly, the novel compounds are suitable, in combination with thevehicles customary in galenic pharmacy, for example, for the treatmentof acute and chronic polyarthritis, neurodermitis, bronchial asthma, hayfever, etc.

The specialty drug preparations are produced in the usual way byconverting the active agents with suitable additives, vehicles, andflavor ameliorating substances into the desired forms of application,such as tablets, dragees, capsules, solutions, inhalants, etc.

In particular, suitable for oral application are tablets, dragees, andcapsules containing, for example, 1-250 mg. of active ingredient and 50mg. to 2 g. of pharmacologically inert carriers, e.g., lactose, amylose,talc, gelatin, magnesium stearate, and similar materials, as well as thecustomary additives. Typical dosages are 1-500 mg./kg. of bodyweight/day for use as an antiinflammatory agent. The administration isfully conventional, e.g., in analogy to that for indomethacin.

The pharmacologically active compounds of Formula I can be processed inaccordance with conventional methods of galenic pharmacy to providemedicinal agents, especially for oral administration. Conventionalexcipients are pharmaceutically acceptable organic or inorganic carriersubstances suitable for parenteral, enteral or topical application whichdo not deleteriously react with the active compounds. Suitablepharmaceutically acceptable carriers include but are not limited towater, salt solutions, alcohols, vegetable oils, polyethylene glycols,gelatine, lactose, amylose, magnesium stearate, talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters,hydroxy-methylcellulose, polyvinyl pyrrolidone, etc. The pharmaceuticalpreparations can be sterilized and if desired mixed with auxiliaryagents, e.g., lubricants, preservatives, stabilizers, wetting agents,emulsifiers, salts for influencing osmotic pressure, buffers, coloring,flavoring and/or aromatic substances and the like which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are solutions,preferably oily or aqueous solutions, as well as suspensions, emulsions,or implants, including suppositories. Ampoules are convenient unitdosages.

For enteral application, particularly suitable are tablets, dragees, orcapsules having talc and/or a carbohydrate carrier or binder or thelike, the carrier preferably being lactose and/or corn starch and/orpotato starch. A syrup, elixir or the like can be used wherein asweetened vehicle is employed. Sustained release compositions can beformulated including those wherein the active compound is protected withdifferentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc.

The specialty drugs are conventionally prepared by formulating theactive agents together with suitable additives into the desired form foradministration. In the thus-formulated medicinal agents, the effectiveagent concentration is dependent on the compound used and the form ofapplication and can be easily determined by clinical tests underconventional considerations.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent.

The following preferred specific embodiments are, therefore, to beconstrued as merely illustrative, and not limitative of the remainder ofthe disclosure in any way whatsoever.

The temperatures hereinbelow are degrees Celsius.

EXAMPLE 1

A mixture of 6.24 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole and3.0 g. of 2-bromoethanol in 100 ml. of absolute ethanol is refluxed for4 hours under exclusion of moisture and an argon atmosphere. Thesolution, cooled to 5°, is neutralized by adding 2 N sodium hydroxidesolution, poured into 900 ml. of ice water, and allowed to stand at icebath temperature until crystallization has been completed. After 45minutes the crystals are removed by vacuum-filtering, washed with icewater, and dried under vacuum at 70°. The crude product isrecrystallized from 250 ml. of ethyl acetate with the addition of asmall amount of activated carbon, thus obtaining 5.38 g. of4,5-bis(4-methoxyphenyl)-2-(2-hydroxyethylthio)imidazole as colorlesscrystals, m.p. 182°.

EXAMPLE 2

3.30 g. of 3-chloroperbenzoic acid, dissolved in 150 ml. ofdichloromethane, is added dropwise to a solution of 5.34 g. of4,5-bis(4-methoxyphenyl)-2-(2-hydroxyethylthio)-imidazole in 1.25 l. ofdichloromethane. The solution is stirred for 24 hours at roomtemperature and then washed with saturated sodium bicarbonate solution.The organic solution is separated and dried over sodium sulfate,whereupon it is concentrated under vacuum. The residue is crystallizedfrom 30 ml. of dioxane with the addition of a small quantity ofactivated carbon, thus obtaining 3.01 g. of4,5-bis(4-methoxyphenyl)-2-(2-hydroxyethylsulfinyl)imidazole, m.p. 184°.

EXAMPLE 3

2.70 g. of 3-chloroperbenzoic acid, dissolved in 120 ml. ofdichloromethane, is added dropwise to a solution of 2.14 g. of4,5-bis(4-methoxyphenyl)-2-(2-hydroxyethylthio)-imidazole in 450 ml. ofdichloromethane. The mixture is stirred for 4 hours at room temperature,washed with saturated sodium bicarbonate solution, the organic phase isseparated, dried over sodium sulfate, and concentrated under vacuum. Theoily residue is recrystallized from 150 ml. of cyclohexane/ether 1:1,thus obtaining 1.68 g. of4,5-bis(4-methoxyphenyl)-2-(2-hydroxyethylsulfonyl)imidazole, m.p. 168°.

EXAMPLE 4

A solution of 7.13 g. of4,5-bis(4-methoxyphenyl)-2-(2-hydroxyethylthio)imidazole in 100 ml. ofabsolute ethanol, wherein 600 mg. of sodium was dissolved, is combinedwith 3.73 g. of methyl iodide in 20 ml. of absolute ethanol. Thesolution is heated for 20 minutes under argon with refluxing. Aftercooling, the solution is poured into 1500 ml. of ice water, neutralizedwith 2 N hydrochloric acid, and extracted with chloroform. The organicphase is dried over sodium sulfate and concentrated under vacuum. Thecrude product is recrystallized from 100 ml. of ethanol with theaddition of a small amount of activated carbon from 1000 ml. ofdiisopropyl ether, thus producing 4.29 g. of4,5-bis(4-methoxyphenyl)-2-(2-hydroxyethylthio)-1-methylimidazole, m.p.127°.

EXAMPLE 5

Under the exclusion of moisture, a solution of 1.43 g. of acetoxyacetylchloride in 50 ml. of absolute tetrahydrofuran is added dropwise at 10°to a solution of 3.57 g. of4,5-bis(4-methoxyphenyl)-2-(2-hydroxyethylthio)imidazole in 100 ml. ofabsolute tetrahydrofuran. After 30 minutes, the reaction mixture isevaporated to dryness under vacuum, the residue is recrystallized fromabsolute ethanol, the thus-precipitated crystals are washed with alcoholand absolute ether, and dried under vacuum at 50°, thus obtaining 3.27g. of O-acetylglycolic acid{2-[4,5-bis(4-methoxyphenyl)-2-imidazolylthio]ethyl}ester,hydrochloride, m.p. 148°-150°.

EXAMPLE 6

3.13 g. of 4,5-bis(4-methoxyphenyl)-2-hydroxyethyl-mercapto-imidazole isheated under reflux in a mixture of 10 ml. of glacial acetic acid and 20ml. of acetic anhydride for 2 hours. The solvent is removed undervacuum. The residue is freed of any remaining acetic anhydride bycodistillation with ethanol. The mixture is again taken up in ethanol,clarified with activated carbon, and after evaporation of the solventthe product is 2.95 g. of4,5-bis(4-methoxyphenyl)-2-(2-acetoxyethylthio)imidazole as a colorlessoil.

C₂₁ H₂₂ N₂ O₄ S (398.484): Calculated: C: 63.30; H: 5.57; N: 7.03; S:8.05. Found: C: 63.42; H: 5.69; N: 6.90; S: 7.92.

EXAMPLE 7

A mixture of 8.65 g. of 4,5-bis(4-fluorophenyl)-2-mercaptoimidazole and4.97 g. of 2-bromoethanol in 150 ml. of absolute ethanol is heated underargon for 4 hours under reflux. The cooled solution is neutralized with2 N sodium hydroxide solution, poured into 800 ml. of ice water, andleft for 45 minutes at ice bath temperature. The crude product isvacuum-filtered, washed with water, and dried under vacuum at 70°. Thecrude product is then recrystallized from 175 ml. of ethyl acetate withthe addition of a small amount of activated carbon, thus obtaining 6.76g. of 4,5-bis(4-fluorophenyl)-2-(2-hydroxyethylthio)imidazole, m.p.192°.

EXAMPLE 8

Under the conditions of Example 2, 0.5 g. of4,5-bis(4-fluorophenyl)-2-(2-hydroxyethylthio)imidazole is oxidized,thus obtaining 0.24 g. of4,5-bis(4-fluorophenyl)-2-(2-hydroxyethylsulfinyl)imidazole, m.p. 182°.

EXAMPLE 9

Under the conditions of Example 3, 0.6 g. of4,5-bis(4-fluorophenyl)-2-(2-hydroxyethylthio)imidazole is oxidized,thus obtaining4,5-bis(4-fluorophenyl)-2-(2-hydroxyethylsulfonyl)imidazole, m.p. 167°.

EXAMPLE 10

A mixture of 8.03 g. of 4,5-bis(4-chlorophenyl)-2-mercaptoimidazole and4.14 g. of 2-bromoethanol in 125 ml. of absolute ethanol is heated underargon for 4 hours with reflux. The cooled solution is neutralized with 2N sodium hydroxide solution, poured into 1200 ml. of ice water, and leftat ice bath temperature for 45 minutes. The crystals arevacuum-filtered, washed with water, and dried under vacuum at 60°. Thecrude product is recrystallized from 500 ml. of acetonitrile with theaddition of a small amount of activated carbon, thus producing 8.76 g.of 4,5-bis(4-chlorophenyl)-2-(2-hydroxyethylthio)imidazole, m.p. 202°.

EXAMPLE 11

Under the conditions of Example 2, 0.5 g. of4,5-bis(4-chlorophenyl)-2-(2-hydroxyethylthio)imidazole is oxidized,thus obtaining 0.38 g. of4,5-bis(4-chlorophenyl)-2-(2-hydroxyethylsulfinyl)imidazole, m.p. 186°.

EXAMPLE 12

Under the conditions of Example 3, 0.5 g. of4,5-bis(4-chlorophenyl)-2-(2-hydroxyethylthio)imidazole is oxidized,thus obtaining 0.41 g. of4,5-bis(4-chlorophenyl)-2-(2-hydroxyethylsulfonyl)imidazole, m.p. 191°.

EXAMPLE 13

A mixture of 4.20 g. of 4,5-bis(p-tolyl)-2-mercaptoimidazole and 2.49 g.of 2-bromoethanol in 75 ml. of absolute ethanol is heated for 4.5 hoursunder argon with refluxing. The solution, cooled to 5°, is neutralizedby adding 2 N sodium hydroxide solution, poured into 800 ml. of icewater, and left at ice bath temperature for 45 minutes. The mixture isthus recrystallized. The crystals are vacuum-filtered, washed withwater, and dried over vacuum at 60°. The crude product is recrystallizedfrom 200 ml. of acetonitrile with the addition of a small amount ofactivated carbon, thus obtaining 3.95 g. of4,5-bis(p-tolyl)-2-(2-hydroxyethylthio)imidazole, m.p. 182°.

EXAMPLE 14

Under the conditions of Example 2, 0.5 g. of4,5-bis(p-tolyl)-2-(2-hydroxyethylthio)imidazole is oxidized, thusobtaining 0.33 g. of4,5-bis(p-tolyl)-2-(2-hydroxyethylsulfinyl)-imidazole, m.p. 169°.

EXAMPLE 15

Under the conditions of Example 3, 0.6 g. of4,5-bis(p-tolyl)-2-(2-hydroxyethylthio)imidazole is oxidized, thusobtaining 0.50 g. of4,5-bis(p-tolyl)-2-(2-hydroxyethylsulfonyl)imidazole, m.p. 166°.

EXAMPLE 16

A solution of 1.25 g. of 4,5-bis(2-pyridyl)-2-mercaptoimidazole in 50ml. of absolute ethanol is combined with 0.69 g. of 2-bromoethanol in 5ml of absolute ethanol. The mixture is heated under reflux and underargon for 8 hours. The solvent is then evaporated under vacuum, thecrystalline residue is vacuum-filtered and washed with absolute ether.Recrystallization from ethyl acetate/hexne yields 1.58 g. of4,5-bis(2-pyridyl)-2-(2-hydroxyethylthio)imidazole, hydrobromide, m.p.249°-250°.

EXAMPLE 17

Under the conditions of Example 2, 0.6 g. of4,5-bis(2-pyridyl)-2-(2-hydroxyethylthio)imidazole is oxidized, thusobtaining 0.42 g. of4,5-bis(2-pyridyl)-2-(2-hydroxyethylsulfinyl)imidazole, m.p. 215°-217°.

EXAMPLE 18

Under the conditions of Example 3, 0.5 g. of4,5-bis(2-pyridyl)-2-(2-hydroxyethylthio)imidazole is oxidized, thusobtaining 0.43 g. of4,5-bis(2-pyridyl)-2-(2-hydroxyethylsulfonyl)imidazole, m.p. 216°.

EXAMPLE 19

1.38 g. of 2-bromoethanol in 10 ml. of absolute ethanol is added to asuspension of 2.64 g. of 4,5-di(2-thienyl)-2-mercaptoimidazole in 50 ml.of absolute ethanol, and the mixture is heated under reflux for 8 hoursunder argon. The solution is allowed to cool off and neutralized with 2N sodium hydroxide solution and then poured into 600 ml. of water. Thethus-precipitated oil is taken up in ethyl acetate. The organic solutionis dried over sodium sulfate and evaporated to dryness under vacuum. Theresidue is recrystallized from ethyl acetate, yielding 2.29 g. of4,5-di(2-thienyl)-2-(2-hydroxyethylthio)imidazole, m.p. 125°.

EXAMPLE 20

Under the conditions of Example 2, 0.5 g. of4,5-di(2-thienyl)-2-(2-hydroxyethylthio)imidazole is oxidized, thusobtaining 0.29 g. of4,5-di(2-thienyl)-2-(2-hydroxyethylsulfinyl)imidazole, m.p. 98°.

EXAMPLE 21

Under the conditions of Example 3, 0.5 g. of4,5-di(2-thienyl)-2-(2-hydroxyethylthio)imidazole is oxidized, yielding0.42 g. of 4,5-di(2-thienyl)-2-(2-hydroxyethylsulfonyl)imidazole, m.p.101°-103°.

EXAMPLE 22

A mixture of 6.25 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole and3.66 g. of 2-bromopropionic acid ethyl ester in 100 ml. of absoluteethanol is heated for 2.5 hours under argon with refluxing. The cooledsolution is neutralized with 2 N sodium hydroxide solution and pouredinto 1000 ml. of ice water. The thus-precipitated oil is taken up inethyl acetate, the solution is dried over sodium sulfate andconcentrated under vacuum, thus obtaining 7.12 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-2-thiopropionic acid ethyl esteras a colorless oil.

Elementary analysis: C₂₂ H₂₄ N₂ O₄ S: (412.52). Calculated: C: 66.64; H:6.10; N: 7.06; S: 8.09. Found: C: 66.41; H: 6.23; N: 7.15; S: 8.21.

EXAMPLE 23

A solution of 8.25 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-2-thiopropionic acid ethyl esterin 150 ml. of absolute tetrahydrofuran is combined with 0.607 g. oflithium aluminum hydride, which latter is added in incremental portions.The mixture is stirred for 30 minutes at room temperature, decomposedwith saturated ammonium chloride solution, and extracted with ethylacetate. After drying the organic solution over sodium sulfate, themixture is concentrated to dryness under vacuum. The crystalline residueis recrystallized from toluene, thus obtaining 5.07 g. of[4,5-bis(4-methoxyphenyl)]-2-(2-hydroxy-1-methylethylthio)imidazole,m.p. 141°.

EXAMPLE 24

At room temperature, a solution of 2.16 g. of 3-chloroperbenzoic acid in150 ml. of chloroform is added dropwise to a solution of 3.71 g. of[4,5-bis(4-methoxyphenyl)]-2-(2-hydroxy-1-methylethylthio)imidazole in200 ml. of chloroform. The mixture is stirred overnight at roomtemperature and washed with saturated sodium bicarbonate solution. Theorganic solution is dried over sodium sulfate and concentrated undervacuum. The residue is purified by chromatography on 200 g. of silicagel with ethyl acetate as the eluent. After evaporation of the solvent,2.67 g. of[4,5-bis(4-methoxyphenyl)]-2-(2-hydroxy-1-methylethylsulfinyl)imidazoleis obtained as an amorphous foam.

C₂₀ H₂₂ N₂ O₄ S: (386.47). Calculated: C: 62.16; H: 5.74; N: 7.25; S:8.30. Found: C: 62.40; H: 5.82; N: 7.19; S: 8.22.

EXAMPLE 25

At room temperature, a solution of 5.20 g. of 3-chloroperbenzoic acid in250 ml. of chloroform is added dropwise to a solution of 3.71 g. of[4,5-bis(4-methoxyphenyl)]-2-(2-hydroxy-1-methylethylthio)imidazole in200 ml. of chloroform. The mixture is stirred overnight at roomtemperature, then washed with saturated sodium bicarbonate solution; theorganic solution is dried over sodium sulfate and concentrated todryness under vacuum, thus obtaining 3.70 g. of[4,5-bis(4-methoxyphenyl)]-2-(2-hydroxy-1-methylethyl-sulfonyl)imidazoleas an amorphous foam, m.p. 68°.

C₂₀ H₂₂ N₂ O₅ S: (402.47). Calculated: C: 59.69; H: 5.51; N: 6.96; S:7.97. Found: C: 59.51; H: 5.61; N: 7.08; S: 7.88.

EXAMPLE 26

A mixture of 9.36 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole and9.13 g. of the ethyl ester of 2-bromoisobutyric acid in 150 ml. ofethanol is heated under reflux for 6 hours under argon. The cooledsolution is neutralized with 2 N sodium hydroxide solution, poured into600 ml. of ice water, and the crude product is extracted withdichloromethane. The organic solution is dried over sodium sulfate andconcentrated to dryness under vacuum. The residue is crystallized fromdichloromethane/diethyl ester, thus obtaining 11.29 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-2-methyl-2-thiopropionic acidethyl ester, m.p. 115°.

EXAMPLE 27

8.53 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-2-methyl-2-thiopropionic acidethyl ester is dissolved in a mixture of respectively 75 ml. of absolutetetrahydrofuran and diethyl ether and combined in incremental portionswith a total of 570 mg. of lithium aluminum hydride. The mixture isstirred at room temperature for 30 minutes, decomposed with saturatedammonium chloride solution, and extracted with ethyl acetate. Afterdrying the organic solution over sodium sulfate, the mixture isconcentrated to dryness under vacuum. Crystallization from tolueneyields 6.33 g. of4,5-bis(4-methoxyphenyl)-2-(1,1-dimethyl-2-hydroxyethylthio)imidazole,m.p. 195°.

EXAMPLE 28

Under the conditions of Example 2, 3.81 g. of4,5-bis(4-methoxyphenyl)-2-(1,1-dimethyl-2-hydroxyethylthio)-imidazoleis oxidized, thus obtaining 2.67 g. of4,5-bis(4-methoxyphenyl)-2-(1,1-dimethyl-2-hydroxyethylsulfinyl)imidazole,m.p. 215°.

EXAMPLE 29

Under the conditions of Example 3, 3.81 g. of4,5-bis(4-methoxyphenyl)-2-(1,1-dimethyl-2-hydroxyethylthio)imidazole isoxidized, thus obtaining 3.22 g. of4,5-bis(4-methoxyphenyl)-2-(1,1-dimethyl-2-hydroxyethylsulfonyl)imidazole,m.p. 187°.

EXAMPLE 30

A solution of 3.95 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole in100 ml. of absolute methanol, wherein 320 mg. of sodium have beendissolved, is combined with 2.14 g. of 2-bromobutyrolactone in 30 ml. ofabsolute methanol, and the mixture is heated under reflux for 2.5 hoursunder argon. After cooling, the solution is poured into 500 ml. of icewater and neutralized with 2 N sulfuric acid. The product is extractedwith ethyl acetate; the organic solution is dried over sodium sulfateand concentrated under vacuum. The residual oil is made to crystallizefrom tetrahydrofuran/hexane, thus obtaining 1.23 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-2-thiobutyrolactone, m.p.140°-142°.

EXAMPLE 31

A solution of 3.96 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-2-thiobutyrolactone in 100 ml.of absolute tetrahydrofuran is combined with 300 mg. of lithium aluminumhydride. The mixture is stirred for 30 minutes at room temperature,decomposed with saturated ammonium chloride solution, and extracted withethyl acetate. After drying the organic solution over sodium sulfate, itis concentrated to dryness under vacuum, thus obtaining 3.26 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-2-thio-1,4-butanediol in theform of a viscous oil.

C₂₁ H₂₄ N₂ O₄ S: (400.50). Calculated: C: 62.98; H: 6.04; N: 7.00; S:8.01. Found: C: 62.71; H: 6.13; N: 6.89; S: 8.17.

EXAMPLE 32

A solution of 6.25 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole in50 ml. of absolute dimethylformamide is combined with 0.96 g. of 50%sodium hydride, and the mixture is agitated for 30 minutes at 60°. Then,2.74 g. of chloroacetaldehyde dimethyl acetal in 20 ml. of absolutedimethylformamide is added to the reaction mixture, and the latter isstirred for 4 hours under argon at 80°. The cooled-off solution ispoured into 700 ml. of water and extracted with chloroform. The organicsolution is dried over sodium sulfate, concentrated to dryness undervacuum, and the dark-brown residue is purified by chromatography on 500g. of silica gel. Elution with ethyl acetate/hexane in a ratio of 1:3yields 5.01 g. of4,5-bis(4-methoxyphenyl)-2-(2,2-dimethoxyethylthio)imidazole as alight-yellow oil.

C₂₁ H₂₄ N₂ O₄ S: (400.50). Calculated: C: 62.98; H: 6.04; N: 7.00; S:8.01. Found: C: 62.69; H: 6.16; N: 7.08; S: 8.11.

EXAMPLE 33

A solution of 1.19 g. of 3-chloroperbenzoic acid in 100 ml. ofdichloromethane is added dropwise to a solution of 2.0 g. of4,5-bis(4-methoxyphenyl)-2-(2,2-dimethoxyethylthio)imidazole in 150 ml.of dichloromethane, and the mixture is agitated for 4 hours at roomtemperature. The mixture is then washed with sodium bicarbonatesolution; the organic solution is dried over sodium sulfate andconcentrated to dryness under vacuum. The residue is crystallized fromethyl acetate/hexane. Recrystallization from ethyl acetate/ethanolyields 1.52 g. of4,5-bis(4-methoxyphenyl)-2-(2,2-dimethoxyethylsulfinyl)imidazole, m.p.127°-128°.

EXAMPLE 34

A solution of 2.97 g. of 3-chloroperbenzoic acid in 100 ml. ofdichloromethane is added dropwise to a solution of 2.5 g. of4,5-bis(4-methoxyphenyl)-2-(2,2-dimethoxyethylthio)-imidazole in 150 ml.of dichloromethane, and the mixture is agitated overnight at roomtemperature. Then the mixture is washed with sodium bicarbonatesolution; the organic solution is dried over sodium sulfate andconcentrated to dryness under vacuum. The residue is crystallized fromethyl acetate/hexane. Recrystallization from ethanol/ether yields 1.96g. of 4,5-bis(4-methoxyphenyl)-2-(2,2-dimethoxyethylsulfonyl)-imidazole,m.p. 78°-80°.

EXAMPLE 35

A solution of 12.48 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazolein 150 ml. of absolute dimethylformamide is combined with 1.92 g. of 50%sodium hydride. After 30 minutes of agitation at 60°, the mixture iscombined with 7.35 g. of bromoacetaldehyde ethylene ketal in 40 ml. ofabsolute dimethylformamide, and the mixture is stirred under argon for 4hours at 90°. The cooled solution is poured into 1000 ml. of water, thethus-separated oil is taken up in ethyl acetate; the organic solution isdried over sodium sulfate and concentrated to dryness under vacuum. Theresidue is recrystallized from ethyl acetate, thus obtaining 11.65 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-1,3-dioxolan-2-ylmethyl)sulfide,m.p. 118°-119°.

EXAMPLE 36

1.19 g (80%) of 3-chloroperbenzoic acid in 100 ml. of dichloromethane isadded dropwise to a solution of 1.99 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)sulfidein 150 ml. of dichloromethane. The mixture is stirred for 4 hours atroom temperature, then washed with sodium bicarbonate solution; theorganic solution is dried over sodium sulfate and concentrated undervacuum. The residue is crystallized from ethyl acetate/hexane. Afterrecrystallization from ethyl acetate/hexane, 1.43 g. of[4,5-bis-(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)-sulfoxideis obtained, m.p. 203°-204°.

EXAMPLE 37

A solution of 2.38 g. (80%) of 3-chloroperbenzoic acid in 150 ml. ofdichloromethane is added dropwise to a solution of 1.99 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)sulfidein 150 ml. of dichloromethane. The mixture is agitated overnight at roomtemperature, then washed with sodium bicarbonate solution, and theorganic solution is dried over sodium sulfate and concentrated undervacuum. The residue is crystallized from ethyl acetate/ethanol.Recrystallization from ethyl acetate/ethanol yields 1.71 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-yl-methyl)sulfone,m.p. 150°.

EXAMPLE 38

Under agitation, 3.95 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazoleis added to a solution of 320 mg. of sodium in 100 ml. of absolutemethanol. The clear, yellow solution is combined with a solution of 2.53g. of bromoacetaldehyde diethyl acetal in 30 ml. of absolute methanol.The mixture is heated for 48 hours under argon with refluxing, is thencooled, and poured into 600 ml. of ice water. The product is extractedwith ethyl acetate. The organic solution is dried over sodium sulfateand concentrated to dryness under vacuum. Unreacted imidazole is removedby crystallization from acetone/hexane. The mother liquor is thenstirred into hexane. The thus-precipitated oil is separated and driedunder an oil pump vacuum at 50°, thus producing 2.93 g. of4,5-bis-(4-methoxyphenyl)-2-(2,2-diethoxyethylthio)imidazole as ayellowish, viscous oil.

C₂₃ H₂₈ N₂ O₄ S: (428.55). Calculated: C: 64.46; H: 6.58; N: 6.54; S:7.48. Found: C: 64.49; H: 6.69; N: 6.48; S: 7.22.

EXAMPLE 39

0.96 g. of 50% sodium hydride is added to a solution of 6.24 g. of4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole in 100 ml. of absolutedimethylformamide, and the mixture is heated to 60° for 30 minutes. Thenthe mixture is combined with a solution of 4.33 g. of bromoacetaldehydediethyl acetal in 20 ml. of absolute dimethylformamide and stirred for 4hours at 80° under argon. The mixture is then allowed to cool, pouredinto 800 ml. of ice water, and extracted with chloroform. The organicsolution is dried over sodium sulfate and concentrated to dryness undervacuum. The residue is treated as described in Example 39, thusobtaining 6.53 g. of4,5-bis-(4-methoxyphenyl)-2-(2,2-diethoxyethylthio)imidazole as a yellowoil.

C₂₃ H₂₈ N₂ O₄ S: (428.55). Calculated: C: 64.46; H: 6.58; N: 6.54; S:7.48. Found: C: 64.53; H: 6.68; N: 6.57; S: 7.31.

EXAMPLE 40

At room temperature, 2.38 g. (80%) of 3-chloroperbenzoic acid in 150 ml.of methylene chloride is added dropwise to a solution of 4.29 g. of4,5-bis(4-methoxyphenyl)-2-(2,2-diethoxyethylthio)imidazole in 150 ml.of methylene chloride. The mixture is stirred for 2 hours at roomtemperature and washed with sodium bicarbonate solution. The organicsolution is dried over sodium sulfate and concentrated under vacuum. Theremaining oil is taken up in diethyl ether and made to crystallize byadding diisopropyl ether, thus obtaining 3.49 g. of4,5-bis(4-methoxyphenyl)-2-(2,2-diethoxyethylsulfinyl)imidazole, m.p.173°-174°.

EXAMPLE 41

At room temperature, 4.76 g. (80%) of 3-chloroperbenzoic acid in 150 ml.of methylene chloride is added dropwise to a solution of 4.29 g. of4,5-bis(4-methoxyphenyl)-2-(2,2-diethoxyethylthio)imidazole in 150 ml.of methylene chloride. The mixture is stirred at room temperature for1.5 hours and washed with sodium bicarbonate solution. The organicsolution is dried over sodium sulfate and concentrated under vacuum. Theremaining oil is treated as described in Example 40, thus producing 3.09g. of 4,5-bis(4-methoxyphenyl)-2-(2,2-diethoxyethylsulfonyl)imidazole,m.p. 149°-150°.

EXAMPLE 42

A solution of 3.95 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole in100 ml. of absolute methanol, wherein 320 mg. of sodium have beendissolved, is combined with 2.53 g. of 3-chloropropanol, and the mixtureis heated under reflux for 24 hours under an argon atmosphere. Thecooled solution is poured into 500 ml. of water, neutralized with 2 Nsulfuric acid, and extracted with chloroform. The organic solution isdried over sodium sulfate, concentrated to dryness under vacuum, and theresidue is crystallized from ethanol, yielding 2.98 g. of4,5-bis(4-methoxyphenyl)-2-(3-hydroxypropylthio)imidazole, m.p. 163°.

EXAMPLE 43

Under agitation, 6.24 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazoleis added to a solution of 506 mg. of sodium in 150 ml. of absoluteethanol. The clear, yellow solution is then combined with a solution of1.24 g. of propylene oxide in 40 ml. of absolute ethanol. The mixture isstirred under argon for 2 hours at room temperature, then poured into600 ml. of ice water. The precipitated crystals are vacuum-filtered,washed with water, and dried under vacuum at 70°, thus obtaining 5.89 g.of 4,5-bis(4-methoxyphenyl)-2-(2-hydroxypropylthio)imidazole, m.p. 163°.

EXAMPLE 44

Under agitation, 6.24 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazoleis added to a solution of 483 mg. of sodium in 100 ml. of absoluteethanol. The clear, yellow solution is then combined with a solution of1.59 g. of isobutene oxide in 30 ml. of absolute ethanol, and themixture is stirred for 3 hours under argon at room temperature. Then themixture is poured into 600 ml. of ice water, the precipitated crystalsare vacuum-filtered, washed with water, and dried under vacuum at 70°.Recrystallization from benzene yields 6.57 g. of4,5-bis(4-methoxyphenyl)-2-(2-hydroxy-2-methylpropylthio)imidazole, m.p.185°.

EXAMPLE 45

3.12 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole is dissolved ina mixture of 40 ml. of dioxane and 40 ml. of tetrahydrofuran and thencombined with 1.08 g. of the ethyl ester of propiolic acid in 10 ml. ofdioxane. After adding 1 ml. of 1 N sodium hydroxide solution, themixture is stirred for 10 minutes under argon. Thereafter the mixture ispoured into 500 ml. of ice water, extracted with chloroform; the organicsolution is dried over sodium sulfate and concentrated to dryness undervacuum. The residue is crystallized from ether/hexane. Recrystallizationfrom ethyl acetate/hexane yields 3.14 g. of[4,5-bis(4-methoxyphenyl)-2-imidazolyl]-3-thiopropenoic acid ethylester, m.p. 206°.

EXAMPLE 46

1.25 g. of 2-bromoethanol in 50 ml. of ethanol is added to a solution of2.95 g. of 4(5)-(4-dimethylaminophenyl)-5(4)-phenyl-2-mercaptoimidazolein 100 ml. of dimethylformamide. The mixture is stirred for 3 hours at75° under argon, is then allowed to cool, and is neutralized with 2 Nsodium hydroxide solution. The solution is introduced into 1000 ml. ofice water and extracted with ethyl acetate. The organic solution isdried over sodium sulfate and concentrated to dryness under vacuum. Theresidue is filtered over 200 g. of silica gel with ethyl acetate/hexane8:2. The concentrated eluate is crystallized from ethyl acetate/hexane.Yield: 2.37 g. of4-(4-dimethylaminophenyl)-5-phenyl-2-(2-hydroxyethylthio)imidazole, m.p.135°-137°.

EXAMPLE 47

A mixture of 7.81 g. of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole and4.87 g. of 2-bromoethyl methyl ether is heated under reflux for 3 hoursin 150 ml. of ethanol. The mixture is allowed to cool, neutralized with2 N sodium hydroxide solution, and poured into 1200 ml. of ice water.The thus-precipitated crystals are vacuum-filtered, washed with water,and dried under vacuum at 50°. The crude product is recrystallized fromethyl acetate, thus obtaining 6.37 g. of4,5-bis(4-methoxyphenyl)-2-(2-methoxyethylthio)imidazole, m.p. 139°.

EXAMPLE 48

One drop of H₂ SO₄ in 1 ml. of absolute tetrahydrofuran is introducedinto a cooled solution of 3.12 g. of4,5-bis(4-methoxyphenyl)-2-(2-hydroxyethylthio)imidazole and 0.7 g. ofmethyl vinyl ether in 150 ml. of absolute tetrahydrofuran. The mixtureis stirred in a sealed vessel overnight at room temperature, thencombined with powdered calcium carbonate, stirred for another 30minutes, diluted with tetrahydrofuran, and the solid matter is filteredoff. The filtrate is concentrated to dryness under vacuum, thusobtaining 3.53 g. of2-[4,5-bis(4-methoxyphenyl)imidazol-2-ylthio]-1'-methoxy diethyl etheras a colorless oil.

C₂₂ H₂₆ N₂ O₄ S: (414.53). Calculated: C: 63.75; H: 6.32; N: 6.76; S:7.74. Found: C: 63.68; H: 6.41; N: 6.67; S: 7.66.

EXAMPLE 49

1.12 g. of propargyl alcohol and 300 mg. of copper(II) chloride areadded to a solution of 6.24 g. of4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole in 50 ml. ofdimethylformamide. The mixture is heated for 12 hours to 120° underargon, then cooled, stirred into ammoniacal ice water, and the productis extracted with ether. The organic solution is dried over sodiumsulfate and concentrated to dryness under vacuum, thus obtaining 4.13 g.of 4,5-bis(4-methoxyphenyl)-2-(3-hydroxy-1-propenylthio)imidazole as anamorphous foam.

C₂₀ H₂₀ N₂ O₃ S: (368.46). Calculated: C: 65.20; H: 5.47; N: 7.60; S:8.70. Found: C: 65.10; H: 5.58; N: 7.49; S: 8.62.

The preceding examples can be repeated with similar success bysubstituting the generically and specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. An imidazole derivative of the formula ##STR6##wherein Ar₁ and Ar₂ are each phenyl; phenyl substituted by halogen, C₁₋₄alkyl, C₁₋₄ alkoxy or C₂₋₆ dialkylamino; with the proviso that Ar₁ andAr₂ are not both unsubstituted phenyl;R₁ is hydrogen, C₁₋₄ alkyl or C₁₋₄alkyl substituted by hydroxy, C₁₋₄ alkoxy or C₁₋₆ alkanoyloxy; n is 0, 1or 2; and Z is a C₂₋₆ -alkenyl residue substituted by one or two ofhydroxy, C₁₋₄ alkoxy, C₂₋₈ alkylenedioxy, C₁₋₆ alkanoyloxy orbenzoyloxy, or by one alkoxycarbonyl group; or C₁₋₆ alkyl substituted bytwo hydroxy or by one or two of C₁₋₄ alkoxy; C₂₋₈ alkylenedioxy; C₁₋₆alkanoyloxy or benzoyloxy; and the salts thereof with physiologicallyacceptable acids.
 2. An imidazole derivative of claim 1, wherein Ar₁ andAr₂ are each phenyl; phenyl substituted in the para position byfluorine, chlorine, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbonatoms or dialkylamino of 2-6 carbon atoms.
 3. An imidazole derivative ofclaim 2, wherein Ar₁ and Ar₂ are each phenyl, 4-fluorophenyl,4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl.4. An imidazole derivative of claim 1, wherein R₁ is hydrogen, alkyl of1-4 carbon atoms, 2-hydroxyethylene or 2-C₁₋₆ -alkanoyloxyethylene. 5.An imidazole derivative of claim 1, wherein n is 1 or
 2. 6. An imidazolederivative of claim 1, wherein Z is a C₂₋₆ -alkyl or C₂₋₆ -alkenylresidue substituted by two hydroxy groups attached to different carbonatoms; by C₁₋₄ alkoxy; by C₁₋₆ alkanoyloxy; or by benzolyoxy; or C₂₋₆alkenyl substituted by one hydroxy.
 7. An imidazole derivative of claim1, wherein Z is a C₁₋₃ -alkyl or -alkenyl residue substituted by1,3-dioxolan-2-yl or by a dialkoxymethylene group of 1-4 carbon atoms ineach alkoxy group.
 8. An imidazole derivative of claim 1, wherein Z is aC₂₋₃ -alkenyl residue substituted by a C₁₋₄ alkoxy-carbonyl group. 9.O-Acetylglycolic acid{2-[4,5-bis(4-methoxyphenyl)-2-imidazolylthio]ethyl} esterhydrochloride. 10.4,5-Bis(4-methoxyphenyl)-2-(2-acetoxyethylthio)imidazole, a compound ofclaim
 1. 11.[4,5-Bis(4-methoxyphenyl)-2-imidazolyl]-2-thio-1,4-butanediol, acompound of claim
 1. 12.4,5-Bis(4-methoxyphenyl)-2-(2,2-dimethoxyethylthio)imidazole, a compoundof claim
 1. 13.4,5-Bis(4-methoxyphenyl)-2-(2,2-dimethoxyethylsulfinyl)imidazole, acompound of claim
 1. 14.4,5-Bis(4-methoxyphenyl)-2-(2,2-dimethoxyethylsulfonyl)imidazole, acompound of claim
 1. 15.[4,5-Bis(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)sulfide,a compound of claim
 1. 16.[4,5-Bis(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)sulfoxide,a compound of claim
 1. 17.[4,5-Bis(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)sulfone,a compound of claim
 1. 18.4,5-Bis(4-methoxyphenyl)-2-(2,2-diethoxyethylthio)imidazole, a compoundof claim
 1. 19.4,5-Bis(4-methoxyphenyl)-2-(2,2-diethoxyethylsulfinyl)imidazole, acompound of claim
 1. 20.4,5-Bis(4-methoxyphenyl)-2-(2,2-diethoxyethylsulfonyl)imidazole, acompound of claim
 1. 21.[4,5-Bis(4-methoxyphenyl)-2-imidazolyl]-3-thiopropenoic acid ethylester, a compound of claim
 1. 22.4,5-Bis(4-methoxyphenyl)-2-(3-hydroxy-1-propenylthio)imidazole, acompound of claim
 1. 23. A pharmaceutical composition comprising anantiinflammatorily effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.
 24. A method of treatinginflammation in a mammal which comprises administering anantiinflammatorily effective amount of a compound of claim 1.